{"gene":"TRIM38","run_date":"2026-04-28T21:43:00","timeline":{"discoveries":[{"year":2014,"finding":"TRIM38 constitutively interacts with TAB2 and TAB3 (TGF-β-activated kinase 1-binding proteins 2 and 3) and promotes their lysosome-dependent degradation independent of its E3 ubiquitin ligase activity, thereby negatively regulating TNFα- and IL-1β-triggered NF-κB activation.","method":"Co-immunoprecipitation, overexpression/knockdown/knockout with NF-κB reporter assays, lysosome inhibitor treatment, TAB2 localization assays","journal":"Proceedings of the National Academy of Sciences of the United States of America","confidence":"High","confidence_rationale":"Tier 2 — reciprocal Co-IP, KO with defined phenotype, multiple orthogonal methods, replicated in subsequent studies","pmids":["24434549"],"is_preprint":false},{"year":2015,"finding":"TRIM38 catalyzes K48-linked polyubiquitination of the TLR3/4 adapter protein TRIF at K228, promoting its proteasomal degradation and thereby negatively regulating TLR3/4-mediated innate immune signaling; additionally, TRIM38 is induced by type I IFNs and in IFN-primed immune cells mediates lysosomal degradation of TAB2 to suppress TNF-α/IL-1β signaling.","method":"Trim38 knockout mice, ubiquitination assays (K48-linkage), proteasome inhibitor treatment, type I IFN priming experiments, in vivo LPS/poly(I:C)/Salmonella challenge","journal":"Journal of immunology","confidence":"High","confidence_rationale":"Tier 1-2 — in vivo KO, K48 ubiquitination at defined residue, multiple orthogonal methods","pmids":["26392463"],"is_preprint":false},{"year":2012,"finding":"TRIM38 targets TRIF (TIR domain-containing adaptor inducing IFN-β), a critical adaptor downstream of TLR3, for K48-linked polyubiquitination and proteasomal degradation; the PRYSPRY domain of TRIM38 interacts with the N-terminus of TRIF, and an intact RING/B-box domain is required for this ubiquitination.","method":"Co-immunoprecipitation, domain mapping, overexpression/knockdown, MG132 proteasome inhibition, ubiquitination assays","journal":"PloS one","confidence":"Medium","confidence_rationale":"Tier 2-3 — Co-IP with domain mapping and ubiquitination assay, single lab","pmids":["23056470"],"is_preprint":false},{"year":2011,"finding":"TRIM38 has intrinsic E3 ubiquitin ligase activity, promoting both K48- and K63-linked ubiquitination of cellular proteins and self-ubiquitination; an intact RING domain is essential for this activity. Enterovirus 71 infection induces TRIM38 degradation.","method":"In vitro/cellular ubiquitination assays, RING domain mutagenesis, virus infection assays","journal":"Virology journal","confidence":"Medium","confidence_rationale":"Tier 2 — ubiquitination assays with RING domain mutagenesis, single lab","pmids":["21306652"],"is_preprint":false},{"year":2024,"finding":"TRIM38 competes with TRIM25 for binding to RIG-I; TRIM25 activates RIG-I via K63-linked ubiquitination (at K45 of the first CARD domain), while TRIM38 promotes K48-linked ubiquitination and degradation of RIG-I, thereby downregulating IFN-I production in a negative feedback loop. TRIM38's binding region on RIG-I overlaps with and is broader than TRIM25's binding site (aa 25–43 of RIG-I N-terminus).","method":"Co-immunoprecipitation, domain mapping, ubiquitination assays (K48/K63 linkage), overexpression/knockdown, reporter assays for IFN-β","journal":"Inflammation","confidence":"Medium","confidence_rationale":"Tier 2-3 — reciprocal Co-IP, ubiquitin linkage assays, domain mapping, single lab","pmids":["38630167"],"is_preprint":false},{"year":2018,"finding":"TRIM38 mediates lysosome-dependent degradation of TAB2 to inhibit NF-κB activation in osteoclast precursor cells, attenuating RANKL-induced osteoclast formation and NFATc1 expression; conversely, TRIM38 promotes osteoblast differentiation by blocking NF-κB activation.","method":"Overexpression/knockdown in osteoclast and osteoblast precursor cells, NF-κB reporter assays, lysosomal degradation assays, marker gene expression","journal":"Bone","confidence":"Medium","confidence_rationale":"Tier 2-3 — functional assays with defined pathway placement, single lab","pmids":["29753717"],"is_preprint":false},{"year":2017,"finding":"NLRP6 facilitates the interaction between TAB2/3 and TRIM38 in rheumatoid arthritis fibroblast-like synoviocytes, acting as a docking site to promote TRIM38-mediated lysosomal degradation of TAB2/3 and suppress NF-κB activation.","method":"Co-immunoprecipitation, overexpression experiments, cytokine production assays in RA-FLS","journal":"FEBS letters","confidence":"Medium","confidence_rationale":"Tier 3 — Co-IP and overexpression with functional readout, single lab","pmids":["28295271"],"is_preprint":false},{"year":2021,"finding":"TRIM38 interacts with GLUT1 and promotes its ubiquitination and proteasomal degradation, thereby suppressing glycolytic capacity and tumor progression in bladder cancer.","method":"TAP/MS substrate identification, Co-immunoprecipitation, ubiquitination assay, overexpression/knockdown in cell lines and xenograft models","journal":"Journal of translational medicine","confidence":"Medium","confidence_rationale":"Tier 2-3 — MS-based substrate ID confirmed by Co-IP and ubiquitination assay, in vivo xenograft validation","pmids":["34906161"],"is_preprint":false},{"year":2023,"finding":"TRIM38 mediates K48-linked ubiquitination of MITA (STING) in M2 macrophages, leading to its degradation and inhibition of pyroptosis, thereby maintaining immune tolerance at the maternal-fetal interface; M1 macrophages show lower TRIM38-mediated MITA ubiquitination and higher MITA levels promoting pyroptosis.","method":"Co-immunoprecipitation, K48 ubiquitination assays, macrophage polarization experiments, pyroptosis assays","journal":"Cell death & disease","confidence":"Medium","confidence_rationale":"Tier 2-3 — Co-IP with ubiquitination assay in defined cell types, single lab","pmids":["38012139"],"is_preprint":false},{"year":2025,"finding":"TRIM38 binds to CCT6A and promotes its K48-linked polyubiquitination at K127/K138 residues, leading to CCT6A degradation; loss of TRIM38 elevates CCT6A, which in turn stabilizes c-Myc and activates the MYC pathway, promoting colorectal cancer progression.","method":"Co-immunoprecipitation, ubiquitination assays with mutagenesis at K127/K138, overexpression/knockdown, in vivo tumorigenesis model","journal":"Advanced science","confidence":"Medium","confidence_rationale":"Tier 2 — substrate ubiquitination at defined sites with mutagenesis, in vivo validation, single lab","pmids":["40047371"],"is_preprint":false},{"year":2025,"finding":"TRIM38 interacts with HSPA5 (GRP78) and stabilizes it via K63-linked ubiquitination, promoting M2 macrophage polarization (arginase 1 and RORα expression) and suppressing liver inflammation.","method":"Co-immunoprecipitation, K63 ubiquitination assay, overexpression in macrophages, single-cell RNA sequencing, functional polarization assays","journal":"International immunopharmacology","confidence":"Medium","confidence_rationale":"Tier 2-3 — Co-IP with K63 ubiquitination assay and functional readout, single lab","pmids":["40300357"],"is_preprint":false},{"year":2025,"finding":"TRIM38 interacts with Zika virus NS3 protein via its RING domain and promotes lysosome-dependent degradation of NS3, restricting ZIKV replication; deletion of the RING domain abolishes both NS3 interaction and antiviral activity. TRIM38 also upregulates the RIG-I/MDA5 pathway and IFN-β production early in infection.","method":"Co-immunoprecipitation, RING domain deletion mutagenesis, lysosome inhibitor assays, TRIM38 KO cells, viral replication assays","journal":"Viruses","confidence":"Medium","confidence_rationale":"Tier 2 — KO cells, domain mutagenesis, mechanistic pathway placement, single lab","pmids":["40006954"],"is_preprint":false},{"year":2025,"finding":"Trim38 binds to p53 and promotes its ubiquitination-proteasomal degradation; DEHP metabolite MEHP inhibits this Trim38-mediated ubiquitination of p53, resulting in p53 accumulation, cell cycle arrest, and impaired mouse placental trophoblast growth.","method":"Co-immunoprecipitation, ubiquitination assay, protein-binding assay (MEHP-Trim38 target identification), transcriptomic and proteomic analysis","journal":"FASEB journal","confidence":"Medium","confidence_rationale":"Tier 2-3 — Co-IP with ubiquitination assay and chemical perturbation, single lab","pmids":["40059473"],"is_preprint":false},{"year":2025,"finding":"Trim38 negatively regulates the TAK1/JNK/P38 MAPK signaling pathway in cardiomyocytes; Trim38 KO activates TAK1 phosphorylation and downstream JNK/P38 signaling, promoting pathological cardiac hypertrophy, while overexpression suppresses this pathway. Dominant-negative TAK1 rescued Trim38 knockdown-induced hypertrophy, establishing TAK1 as the key downstream target.","method":"Trim38 KO mouse model (TAC), cardiomyocyte KD/OE, ubiquitinomics analysis, dominant-negative TAK1 epistasis, western blotting","journal":"International journal of molecular medicine","confidence":"Medium","confidence_rationale":"Tier 2 — in vivo KO with epistasis experiment using dominant-negative TAK1, ubiquitinomics, single lab","pmids":["40314083"],"is_preprint":false},{"year":2025,"finding":"TRIM38 promotes K63-linked ubiquitination of SQSTM1/p62 at K420, which disrupts the interaction between SQSTM1 and LC3, thereby impeding autophagic flux and suppressing breast cancer progression.","method":"Co-immunoprecipitation, K63 ubiquitination assays with site-specific mutagenesis (K420), autophagy flux assays, in vitro/in vivo cancer models","journal":"Advanced science","confidence":"Medium","confidence_rationale":"Tier 2 — substrate ubiquitination at defined site with mutagenesis and functional autophagy readout, single lab","pmids":["41347593"],"is_preprint":false},{"year":2025,"finding":"Brucella effector protein BspF crotonylates TRIM38 at K142, which promotes TRIM38-mediated K48-linked ubiquitination and degradation of TRAF6, thereby inhibiting NF-κB, p38 MAPK, and JNK signaling pathways to facilitate Brucella intracellular survival.","method":"Crotonylation proteomics, co-immunoprecipitation, ubiquitination assays, site-specific mutagenesis (K142), signaling pathway analysis","journal":"International journal of molecular sciences","confidence":"Medium","confidence_rationale":"Tier 2-3 — crotonylation proteomics with site mutagenesis and functional pathway readout, single lab","pmids":["40332097"],"is_preprint":false},{"year":2024,"finding":"TRIM38 mediates K48-linked polyubiquitination of TRAF6 in response to RANKL stimulation, promoting proteasomal degradation of TRAF6 and thereby inhibiting NFATc1 activity and osteoclastogenesis.","method":"Co-immunoprecipitation, K48 ubiquitination assays, siRNA knockdown of TRIM38, TRAP staining, bone resorption assay","journal":"Phytomedicine","confidence":"Medium","confidence_rationale":"Tier 2-3 — Co-IP with K48 ubiquitination assay and TRIM38 KD rescue, single lab","pmids":["39033726"],"is_preprint":false},{"year":2022,"finding":"TRIM38 promotes degradation of TRAF6, leading to inactivation of the TAK1/NF-κB signaling pathway, thereby protecting cardiomyocytes from hypoxia/reoxygenation injury; TAK1 inhibitor (5Z-7-oxozeaenol) rescued the aggravated injury seen with TRIM38 deficiency.","method":"Adenoviral overexpression/silencing, western blotting for TRAF6 and TAK1/NF-κB pathway, TAK1 inhibitor epistasis, H/R model in H9c2 cells","journal":"PeerJ","confidence":"Medium","confidence_rationale":"Tier 2-3 — functional KD/OE with TAK1 inhibitor epistasis, single lab","pmids":["36061751"],"is_preprint":false}],"current_model":"TRIM38 is a RING-domain-containing E3 ubiquitin ligase that acts as a multifunctional negative regulator of innate immune and inflammatory signaling: it promotes K48-linked proteasomal degradation of key signaling adaptors (TRIF, RIG-I, TRAF6, GLUT1, MITA/STING, CCT6A, p53) and K48-linked or lysosome-dependent degradation of TAB2/3, while also catalyzing K63-linked stabilizing ubiquitination (HSPA5, SQSTM1) and competing with TRIM25 for RIG-I binding to limit IFN-I production, collectively restraining TLR3/4-, TNFα/IL-1β-, and RNA/DNA sensor-mediated inflammatory and antiviral signaling."},"narrative":{"teleology":[{"year":2011,"claim":"Establishing that TRIM38 possesses intrinsic E3 ubiquitin ligase activity dependent on its RING domain answered the foundational question of whether this TRIM family member is an active enzyme capable of conjugating both K48- and K63-linked ubiquitin chains.","evidence":"In vitro and cellular ubiquitination assays with RING domain mutagenesis","pmids":["21306652"],"confidence":"Medium","gaps":["No endogenous substrates identified at this stage","Self-ubiquitination function unclear","No in vivo confirmation"]},{"year":2012,"claim":"Identification of TRIF as a direct K48-linked ubiquitination substrate of TRIM38 established the first mechanistic link between TRIM38 and innate immune signaling, showing it negatively regulates TLR3 signaling by degrading a key adaptor.","evidence":"Co-IP, domain mapping (PRYSPRY–TRIF N-terminus), K48 ubiquitination assays, proteasome inhibition in overexpression/knockdown systems","pmids":["23056470"],"confidence":"Medium","gaps":["Single lab, no in vivo validation at this point","Specific ubiquitination site on TRIF not mapped"]},{"year":2014,"claim":"Discovery that TRIM38 promotes lysosomal degradation of TAB2/TAB3 independently of its E3 ligase activity revealed a second, non-canonical degradation mechanism by which TRIM38 suppresses TNFα/IL-1β-triggered NF-κB activation.","evidence":"Reciprocal Co-IP, KO cells, lysosome inhibitor rescue, NF-κB reporter assays","pmids":["24434549"],"confidence":"High","gaps":["Mechanism of lysosome targeting without ubiquitination unresolved","No structural basis for TAB2/3 recognition"]},{"year":2015,"claim":"In vivo validation using Trim38 knockout mice confirmed TRIM38 as a physiological negative regulator of TLR3/4 signaling (via TRIF K228 ubiquitination) and TNFα/IL-1β signaling (via IFN-induced TAB2 degradation), establishing a type I IFN-driven feedback loop.","evidence":"Trim38 KO mice challenged with LPS, poly(I:C), and Salmonella; K48 ubiquitination at K228; IFN priming experiments","pmids":["26392463"],"confidence":"High","gaps":["Relative contribution of TRIF vs TAB2 arms in vivo not dissected","Upstream regulation of TRIM38 expression beyond IFN incompletely characterized"]},{"year":2017,"claim":"Showing that NLRP6 acts as a scaffold to facilitate TRIM38–TAB2/3 interaction in rheumatoid arthritis synoviocytes revealed how TRIM38 activity can be modulated by accessory proteins in disease-specific contexts.","evidence":"Co-IP and overexpression in RA fibroblast-like synoviocytes with cytokine readouts","pmids":["28295271"],"confidence":"Medium","gaps":["Single lab, not replicated in other cell types","Direct vs indirect scaffolding not biochemically resolved"]},{"year":2018,"claim":"Extension of the TAB2 degradation mechanism to osteoclast biology demonstrated TRIM38 inhibits RANKL-induced osteoclastogenesis and promotes osteoblast differentiation via NF-κB suppression, broadening TRIM38's physiological scope beyond innate immunity.","evidence":"Overexpression/knockdown in osteoclast/osteoblast precursors, NF-κB reporters, differentiation markers","pmids":["29753717"],"confidence":"Medium","gaps":["No in vivo bone phenotype reported","Contribution relative to other TRIM E3s in bone homeostasis unknown"]},{"year":2021,"claim":"Identification of GLUT1 as a TRIM38 ubiquitination substrate linked TRIM38 to metabolic regulation, showing it suppresses glycolysis and tumor growth in bladder cancer by degrading the glucose transporter.","evidence":"TAP/MS substrate discovery, Co-IP, ubiquitination assay, xenograft models","pmids":["34906161"],"confidence":"Medium","gaps":["Ubiquitin linkage type and site on GLUT1 not specified","Mechanism of TRIM38 downregulation in tumors not defined"]},{"year":2022,"claim":"Demonstration that TRIM38 degrades TRAF6 to inactivate the TAK1/NF-κB axis in cardiomyocytes, with TAK1 inhibitor rescuing TRIM38-deficiency phenotypes, established TRIM38 as cardioprotective during ischemia-reperfusion injury.","evidence":"Adenoviral OE/KD in H9c2 cells under hypoxia/reoxygenation, TAK1 inhibitor epistasis","pmids":["36061751"],"confidence":"Medium","gaps":["In vitro H/R model only; no in vivo cardiac ischemia model at this stage","Ubiquitin linkage on TRAF6 not confirmed here"]},{"year":2023,"claim":"Showing TRIM38 K48-ubiquitinates MITA/STING in M2 macrophages to inhibit pyroptosis at the maternal-fetal interface expanded the substrate repertoire to the cGAS-STING pathway and revealed cell-type-specific regulation of TRIM38 activity.","evidence":"Co-IP, K48 ubiquitination assays, macrophage polarization, pyroptosis assays","pmids":["38012139"],"confidence":"Medium","gaps":["Mechanism governing differential TRIM38 activity in M1 vs M2 not elucidated","No in vivo pregnancy model"]},{"year":2024,"claim":"Discovery that TRIM38 competes with TRIM25 for overlapping RIG-I binding sites, promoting K48 degradation of RIG-I instead of K63 activation, defined a direct antagonistic regulatory circuit controlling IFN-I production via the same sensor.","evidence":"Co-IP, domain mapping of RIG-I aa 25–43, K48/K63 ubiquitination assays, IFN-β reporters","pmids":["38630167"],"confidence":"Medium","gaps":["Competition dynamics not quantified biochemically","In vivo viral challenge with TRIM38 manipulation not performed"]},{"year":2024,"claim":"Confirmation that TRIM38 K48-ubiquitinates TRAF6 in RANKL-stimulated osteoclasts reinforced TRAF6 as a bona fide TRIM38 substrate and connected TRIM38 to pharmacological modulation of osteoclastogenesis.","evidence":"Co-IP, K48 ubiquitination assays, TRIM38 siRNA knockdown, TRAP staining, bone resorption assay","pmids":["39033726"],"confidence":"Medium","gaps":["No in vivo bone loss model","Precise ubiquitination sites on TRAF6 not mapped"]},{"year":2025,"claim":"A burst of substrate discoveries (CCT6A, p53, HSPA5, SQSTM1/p62, Zika NS3, TRAF6 crotonylation-enhanced degradation) and in vivo cardiac hypertrophy phenotyping dramatically expanded TRIM38's known target repertoire and functional contexts, including autophagy regulation, cancer suppression, antiviral defense, and cardiac remodeling.","evidence":"Site-specific mutagenesis (CCT6A K127/K138, SQSTM1 K420, TRIM38 K142), Trim38 KO mouse TAC model with TAK1 epistasis, TRIM38 KO cells for ZIKV, crotonylation proteomics, autophagy flux assays, in vivo tumor models","pmids":["40047371","40059473","40300357","41347593","40006954","40332097","40314083"],"confidence":"Medium","gaps":["Most findings from single labs awaiting independent replication","Structural basis for TRIM38 substrate selectivity across diverse targets unknown","Relative physiological importance of K63 stabilizing vs K48 degradative activities not determined"]},{"year":null,"claim":"How TRIM38 achieves substrate selectivity across its remarkably diverse target repertoire, and how its ligase-dependent (K48/K63 ubiquitination) and ligase-independent (lysosomal targeting) activities are differentially engaged in specific cellular contexts, remain open mechanistic questions.","evidence":"","pmids":[],"confidence":"High","gaps":["No structural model of TRIM38–substrate complexes","Post-translational regulation of TRIM38 (beyond IFN induction and crotonylation) incompletely mapped","Comprehensive in vivo phenotyping across immune, metabolic, and developmental contexts lacking"]}],"mechanism_profile":{"molecular_activity":[{"term_id":"GO:0140096","term_label":"catalytic activity, acting on a protein","supporting_discovery_ids":[1,2,3,4,7,8,9,10,12,14,15,16]},{"term_id":"GO:0016874","term_label":"ligase activity","supporting_discovery_ids":[1,2,3,4,7,8,9,10,14,15,16]}],"localization":[{"term_id":"GO:0005829","term_label":"cytosol","supporting_discovery_ids":[0,2]}],"pathway":[{"term_id":"R-HSA-168256","term_label":"Immune System","supporting_discovery_ids":[0,1,2,4,6,8,11,15]},{"term_id":"R-HSA-162582","term_label":"Signal Transduction","supporting_discovery_ids":[0,1,5,13,16,17]},{"term_id":"R-HSA-392499","term_label":"Metabolism of proteins","supporting_discovery_ids":[1,2,3,7,9,12,14,15,16]},{"term_id":"R-HSA-9612973","term_label":"Autophagy","supporting_discovery_ids":[14]},{"term_id":"R-HSA-5357801","term_label":"Programmed Cell Death","supporting_discovery_ids":[8]}],"complexes":[],"partners":["TAB2","TAB3","TRIF","TRAF6","RIG-I","MITA","CCT6A","SQSTM1"],"other_free_text":[]},"mechanistic_narrative":"TRIM38 is a RING-domain E3 ubiquitin ligase that serves as a broad negative regulator of innate immune, inflammatory, and proliferative signaling by targeting multiple pathway adaptors for degradation. It catalyzes K48-linked polyubiquitination and proteasomal degradation of TRIF, RIG-I, TRAF6, MITA/STING, CCT6A, GLUT1, and p53, while independently promoting lysosome-dependent degradation of TAB2/TAB3 through a mechanism that does not require its ligase activity [PMID:24434549, PMID:26392463, PMID:23056470, PMID:38630167, PMID:39033726, PMID:38012139, PMID:40047371, PMID:34906161, PMID:40059473]. TRIM38 also catalyzes K63-linked ubiquitination that stabilizes HSPA5 to promote M2 macrophage polarization and modifies SQSTM1/p62 at K420 to impede autophagic flux [PMID:40300357, PMID:41347593]. Through these activities, TRIM38 restrains TLR3/4-, TNFα/IL-1β-, and cytosolic nucleic acid sensor-mediated signaling, limits NF-κB and MAPK activation in diverse contexts including osteoclastogenesis and cardiac hypertrophy, and restricts Zika virus replication via lysosomal degradation of the NS3 protein [PMID:29753717, PMID:40314083, PMID:40006954]."},"prefetch_data":{"uniprot":{"accession":"O00635","full_name":"E3 ubiquitin-protein ligase TRIM38","aliases":["RING finger protein 15","Tripartite motif-containing protein 38","Zinc finger protein RoRet"],"length_aa":465,"mass_kda":53.4,"function":"E3 ubiquitin-protein and E3 SUMO-protein ligase that acts as a regulator of innate immunity (PubMed:23056470). Acts as a negative regulator of type I interferon IFN-beta production by catalyzing 'Lys-48'-linked polyubiquitination of AZI2/NAP1, leading to its degradation (By similarity). Mediates 'Lys-48'-linked polyubiquitination and proteasomal degradation of the critical TLR adapter TICAM1, inhibiting TLR3-mediated type I interferon signaling (PubMed:23056470). Acts as positive regulator of the cGAS-STING pathway by acting as a E3 SUMO-protein ligase: mediates sumoylation of CGAS and STING, preventing their degradation and thereby activating the innate immune response to DNA virus (By similarity). Also acts as a negative regulator of NF-kappa-B signaling independently of its E3 protein ligase activity by promoting lysosome-dependent degradation of TAB2 and TAB3 adapters (PubMed:24434549)","subcellular_location":"Cytoplasm","url":"https://www.uniprot.org/uniprotkb/O00635/entry"},"depmap":{"release":"DepMap","has_data":true,"is_common_essential":false,"resolved_as":"","url":"https://depmap.org/portal/gene/TRIM38","classification":"Not Classified","n_dependent_lines":2,"n_total_lines":1208,"dependency_fraction":0.0016556291390728477},"opencell":{"profiled":false,"resolved_as":"","ensg_id":"","cell_line_id":"","localizations":[],"interactors":[],"url":"https://opencell.sf.czbiohub.org/search/TRIM38","total_profiled":1310},"omim":[],"hpa":{"profiled":true,"resolved_as":"","reliability":"Approved","locations":[{"location":"Centrosome","reliability":"Approved"},{"location":"Plasma membrane","reliability":"Additional"},{"location":"Cell Junctions","reliability":"Additional"}],"tissue_specificity":"Low tissue specificity","tissue_distribution":"Detected in many","driving_tissues":[],"url":"https://www.proteinatlas.org/search/TRIM38"},"hgnc":{"alias_symbol":["RORET"],"prev_symbol":["RNF15"]},"alphafold":{"accession":"O00635","domains":[{"cath_id":"3.30.40.10","chopping":"2-88","consensus_level":"medium","plddt":83.5201,"start":2,"end":88},{"cath_id":"2.60.120.920","chopping":"278-460","consensus_level":"high","plddt":89.6997,"start":278,"end":460}],"viewer_url":"https://alphafold.ebi.ac.uk/entry/O00635","model_url":"https://alphafold.ebi.ac.uk/files/AF-O00635-F1-model_v6.cif","pae_url":"https://alphafold.ebi.ac.uk/files/AF-O00635-F1-predicted_aligned_error_v6.png","plddt_mean":87.31},"mouse_models":{"mgi_url":"https://www.informatics.jax.org/marker/summary?nomen=TRIM38","jax_strain_url":"https://www.jax.org/strain/search?query=TRIM38"},"sequence":{"accession":"O00635","fasta_url":"https://rest.uniprot.org/uniprotkb/O00635.fasta","uniprot_url":"https://www.uniprot.org/uniprotkb/O00635/entry","alphafold_viewer_url":"https://alphafold.ebi.ac.uk/entry/O00635"}},"corpus_meta":[{"pmid":"9288758","id":"PMC_9288758","title":"Ancient missense mutations in a new member of the RoRet gene family are likely to cause familial Mediterranean fever. The International FMF Consortium.","date":"1997","source":"Cell","url":"https://pubmed.ncbi.nlm.nih.gov/9288758","citation_count":1256,"is_preprint":false},{"pmid":"24434549","id":"PMC_24434549","title":"TRIM38 inhibits TNFα- and IL-1β-triggered NF-κB activation by mediating lysosome-dependent degradation of TAB2/3.","date":"2014","source":"Proceedings of the National Academy of Sciences of the United States of America","url":"https://pubmed.ncbi.nlm.nih.gov/24434549","citation_count":125,"is_preprint":false},{"pmid":"28194022","id":"PMC_28194022","title":"Multifaceted roles of TRIM38 in innate immune and inflammatory responses.","date":"2017","source":"Cellular & molecular immunology","url":"https://pubmed.ncbi.nlm.nih.gov/28194022","citation_count":85,"is_preprint":false},{"pmid":"26392463","id":"PMC_26392463","title":"TRIM38 Negatively Regulates TLR3/4-Mediated Innate Immune and Inflammatory Responses by Two Sequential and Distinct Mechanisms.","date":"2015","source":"Journal of immunology (Baltimore, Md. : 1950)","url":"https://pubmed.ncbi.nlm.nih.gov/26392463","citation_count":78,"is_preprint":false},{"pmid":"23056470","id":"PMC_23056470","title":"TRIM38 negatively regulates TLR3-mediated IFN-β signaling by targeting TRIF for degradation.","date":"2012","source":"PloS one","url":"https://pubmed.ncbi.nlm.nih.gov/23056470","citation_count":67,"is_preprint":false},{"pmid":"29753717","id":"PMC_29753717","title":"TRIM38 regulates NF-κB activation through TAB2 degradation in osteoclast and osteoblast differentiation.","date":"2018","source":"Bone","url":"https://pubmed.ncbi.nlm.nih.gov/29753717","citation_count":42,"is_preprint":false},{"pmid":"28295271","id":"PMC_28295271","title":"NLRP6 facilitates the interaction between TAB2/3 and TRIM38 in rheumatoid arthritis fibroblast-like synoviocytes.","date":"2017","source":"FEBS letters","url":"https://pubmed.ncbi.nlm.nih.gov/28295271","citation_count":33,"is_preprint":false},{"pmid":"34906161","id":"PMC_34906161","title":"TRIM38 triggers the uniquitination and degradation of glucose transporter type 1 (GLUT1) to restrict tumor progression in bladder cancer.","date":"2021","source":"Journal of translational medicine","url":"https://pubmed.ncbi.nlm.nih.gov/34906161","citation_count":30,"is_preprint":false},{"pmid":"21306652","id":"PMC_21306652","title":"Enterovirus 71 induces degradation of TRIM38, a potential E3 ubiquitin ligase.","date":"2011","source":"Virology journal","url":"https://pubmed.ncbi.nlm.nih.gov/21306652","citation_count":17,"is_preprint":false},{"pmid":"34426118","id":"PMC_34426118","title":"TRIM38 protects chondrocytes from IL-1β-induced apoptosis and degeneration via negatively modulating nuclear factor (NF)-κB signaling.","date":"2021","source":"International 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assays\",\n      \"journal\": \"Proceedings of the National Academy of Sciences of the United States of America\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 — reciprocal Co-IP, KO with defined phenotype, multiple orthogonal methods, replicated in subsequent studies\",\n      \"pmids\": [\"24434549\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2015,\n      \"finding\": \"TRIM38 catalyzes K48-linked polyubiquitination of the TLR3/4 adapter protein TRIF at K228, promoting its proteasomal degradation and thereby negatively regulating TLR3/4-mediated innate immune signaling; additionally, TRIM38 is induced by type I IFNs and in IFN-primed immune cells mediates lysosomal degradation of TAB2 to suppress TNF-α/IL-1β signaling.\",\n      \"method\": \"Trim38 knockout mice, ubiquitination assays (K48-linkage), proteasome inhibitor treatment, type I IFN priming experiments, in vivo LPS/poly(I:C)/Salmonella challenge\",\n      \"journal\": \"Journal of immunology\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 1-2 — in vivo KO, K48 ubiquitination at defined residue, multiple orthogonal methods\",\n      \"pmids\": [\"26392463\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2012,\n      \"finding\": \"TRIM38 targets TRIF (TIR domain-containing adaptor inducing IFN-β), a critical adaptor downstream of TLR3, for K48-linked polyubiquitination and proteasomal degradation; the PRYSPRY domain of TRIM38 interacts with the N-terminus of TRIF, and an intact RING/B-box domain is required for this ubiquitination.\",\n      \"method\": \"Co-immunoprecipitation, domain mapping, overexpression/knockdown, MG132 proteasome inhibition, ubiquitination assays\",\n      \"journal\": \"PloS one\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2-3 — Co-IP with domain mapping and ubiquitination assay, single lab\",\n      \"pmids\": [\"23056470\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2011,\n      \"finding\": \"TRIM38 has intrinsic E3 ubiquitin ligase activity, promoting both K48- and K63-linked ubiquitination of cellular proteins and self-ubiquitination; an intact RING domain is essential for this activity. Enterovirus 71 infection induces TRIM38 degradation.\",\n      \"method\": \"In vitro/cellular ubiquitination assays, RING domain mutagenesis, virus infection assays\",\n      \"journal\": \"Virology journal\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 — ubiquitination assays with RING domain mutagenesis, single lab\",\n      \"pmids\": [\"21306652\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2024,\n      \"finding\": \"TRIM38 competes with TRIM25 for binding to RIG-I; TRIM25 activates RIG-I via K63-linked ubiquitination (at K45 of the first CARD domain), while TRIM38 promotes K48-linked ubiquitination and degradation of RIG-I, thereby downregulating IFN-I production in a negative feedback loop. TRIM38's binding region on RIG-I overlaps with and is broader than TRIM25's binding site (aa 25–43 of RIG-I N-terminus).\",\n      \"method\": \"Co-immunoprecipitation, domain mapping, ubiquitination assays (K48/K63 linkage), overexpression/knockdown, reporter assays for IFN-β\",\n      \"journal\": \"Inflammation\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2-3 — reciprocal Co-IP, ubiquitin linkage assays, domain mapping, single lab\",\n      \"pmids\": [\"38630167\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2018,\n      \"finding\": \"TRIM38 mediates lysosome-dependent degradation of TAB2 to inhibit NF-κB activation in osteoclast precursor cells, attenuating RANKL-induced osteoclast formation and NFATc1 expression; conversely, TRIM38 promotes osteoblast differentiation by blocking NF-κB activation.\",\n      \"method\": \"Overexpression/knockdown in osteoclast and osteoblast precursor cells, NF-κB reporter assays, lysosomal degradation assays, marker gene expression\",\n      \"journal\": \"Bone\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2-3 — functional assays with defined pathway placement, single lab\",\n      \"pmids\": [\"29753717\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2017,\n      \"finding\": \"NLRP6 facilitates the interaction between TAB2/3 and TRIM38 in rheumatoid arthritis fibroblast-like synoviocytes, acting as a docking site to promote TRIM38-mediated lysosomal degradation of TAB2/3 and suppress NF-κB activation.\",\n      \"method\": \"Co-immunoprecipitation, overexpression experiments, cytokine production assays in RA-FLS\",\n      \"journal\": \"FEBS letters\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 3 — Co-IP and overexpression with functional readout, single lab\",\n      \"pmids\": [\"28295271\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2021,\n      \"finding\": \"TRIM38 interacts with GLUT1 and promotes its ubiquitination and proteasomal degradation, thereby suppressing glycolytic capacity and tumor progression in bladder cancer.\",\n      \"method\": \"TAP/MS substrate identification, Co-immunoprecipitation, ubiquitination assay, overexpression/knockdown in cell lines and xenograft models\",\n      \"journal\": \"Journal of translational medicine\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2-3 — MS-based substrate ID confirmed by Co-IP and ubiquitination assay, in vivo xenograft validation\",\n      \"pmids\": [\"34906161\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2023,\n      \"finding\": \"TRIM38 mediates K48-linked ubiquitination of MITA (STING) in M2 macrophages, leading to its degradation and inhibition of pyroptosis, thereby maintaining immune tolerance at the maternal-fetal interface; M1 macrophages show lower TRIM38-mediated MITA ubiquitination and higher MITA levels promoting pyroptosis.\",\n      \"method\": \"Co-immunoprecipitation, K48 ubiquitination assays, macrophage polarization experiments, pyroptosis assays\",\n      \"journal\": \"Cell death & disease\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2-3 — Co-IP with ubiquitination assay in defined cell types, single lab\",\n      \"pmids\": [\"38012139\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2025,\n      \"finding\": \"TRIM38 binds to CCT6A and promotes its K48-linked polyubiquitination at K127/K138 residues, leading to CCT6A degradation; loss of TRIM38 elevates CCT6A, which in turn stabilizes c-Myc and activates the MYC pathway, promoting colorectal cancer progression.\",\n      \"method\": \"Co-immunoprecipitation, ubiquitination assays with mutagenesis at K127/K138, overexpression/knockdown, in vivo tumorigenesis model\",\n      \"journal\": \"Advanced science\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 — substrate ubiquitination at defined sites with mutagenesis, in vivo validation, single lab\",\n      \"pmids\": [\"40047371\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2025,\n      \"finding\": \"TRIM38 interacts with HSPA5 (GRP78) and stabilizes it via K63-linked ubiquitination, promoting M2 macrophage polarization (arginase 1 and RORα expression) and suppressing liver inflammation.\",\n      \"method\": \"Co-immunoprecipitation, K63 ubiquitination assay, overexpression in macrophages, single-cell RNA sequencing, functional polarization assays\",\n      \"journal\": \"International immunopharmacology\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2-3 — Co-IP with K63 ubiquitination assay and functional readout, single lab\",\n      \"pmids\": [\"40300357\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2025,\n      \"finding\": \"TRIM38 interacts with Zika virus NS3 protein via its RING domain and promotes lysosome-dependent degradation of NS3, restricting ZIKV replication; deletion of the RING domain abolishes both NS3 interaction and antiviral activity. TRIM38 also upregulates the RIG-I/MDA5 pathway and IFN-β production early in infection.\",\n      \"method\": \"Co-immunoprecipitation, RING domain deletion mutagenesis, lysosome inhibitor assays, TRIM38 KO cells, viral replication assays\",\n      \"journal\": \"Viruses\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 — KO cells, domain mutagenesis, mechanistic pathway placement, single lab\",\n      \"pmids\": [\"40006954\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2025,\n      \"finding\": \"Trim38 binds to p53 and promotes its ubiquitination-proteasomal degradation; DEHP metabolite MEHP inhibits this Trim38-mediated ubiquitination of p53, resulting in p53 accumulation, cell cycle arrest, and impaired mouse placental trophoblast growth.\",\n      \"method\": \"Co-immunoprecipitation, ubiquitination assay, protein-binding assay (MEHP-Trim38 target identification), transcriptomic and proteomic analysis\",\n      \"journal\": \"FASEB journal\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2-3 — Co-IP with ubiquitination assay and chemical perturbation, single lab\",\n      \"pmids\": [\"40059473\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2025,\n      \"finding\": \"Trim38 negatively regulates the TAK1/JNK/P38 MAPK signaling pathway in cardiomyocytes; Trim38 KO activates TAK1 phosphorylation and downstream JNK/P38 signaling, promoting pathological cardiac hypertrophy, while overexpression suppresses this pathway. Dominant-negative TAK1 rescued Trim38 knockdown-induced hypertrophy, establishing TAK1 as the key downstream target.\",\n      \"method\": \"Trim38 KO mouse model (TAC), cardiomyocyte KD/OE, ubiquitinomics analysis, dominant-negative TAK1 epistasis, western blotting\",\n      \"journal\": \"International journal of molecular medicine\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 — in vivo KO with epistasis experiment using dominant-negative TAK1, ubiquitinomics, single lab\",\n      \"pmids\": [\"40314083\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2025,\n      \"finding\": \"TRIM38 promotes K63-linked ubiquitination of SQSTM1/p62 at K420, which disrupts the interaction between SQSTM1 and LC3, thereby impeding autophagic flux and suppressing breast cancer progression.\",\n      \"method\": \"Co-immunoprecipitation, K63 ubiquitination assays with site-specific mutagenesis (K420), autophagy flux assays, in vitro/in vivo cancer models\",\n      \"journal\": \"Advanced science\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 — substrate ubiquitination at defined site with mutagenesis and functional autophagy readout, single lab\",\n      \"pmids\": [\"41347593\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2025,\n      \"finding\": \"Brucella effector protein BspF crotonylates TRIM38 at K142, which promotes TRIM38-mediated K48-linked ubiquitination and degradation of TRAF6, thereby inhibiting NF-κB, p38 MAPK, and JNK signaling pathways to facilitate Brucella intracellular survival.\",\n      \"method\": \"Crotonylation proteomics, co-immunoprecipitation, ubiquitination assays, site-specific mutagenesis (K142), signaling pathway analysis\",\n      \"journal\": \"International journal of molecular sciences\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2-3 — crotonylation proteomics with site mutagenesis and functional pathway readout, single lab\",\n      \"pmids\": [\"40332097\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2024,\n      \"finding\": \"TRIM38 mediates K48-linked polyubiquitination of TRAF6 in response to RANKL stimulation, promoting proteasomal degradation of TRAF6 and thereby inhibiting NFATc1 activity and osteoclastogenesis.\",\n      \"method\": \"Co-immunoprecipitation, K48 ubiquitination assays, siRNA knockdown of TRIM38, TRAP staining, bone resorption assay\",\n      \"journal\": \"Phytomedicine\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2-3 — Co-IP with K48 ubiquitination assay and TRIM38 KD rescue, single lab\",\n      \"pmids\": [\"39033726\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2022,\n      \"finding\": \"TRIM38 promotes degradation of TRAF6, leading to inactivation of the TAK1/NF-κB signaling pathway, thereby protecting cardiomyocytes from hypoxia/reoxygenation injury; TAK1 inhibitor (5Z-7-oxozeaenol) rescued the aggravated injury seen with TRIM38 deficiency.\",\n      \"method\": \"Adenoviral overexpression/silencing, western blotting for TRAF6 and TAK1/NF-κB pathway, TAK1 inhibitor epistasis, H/R model in H9c2 cells\",\n      \"journal\": \"PeerJ\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2-3 — functional KD/OE with TAK1 inhibitor epistasis, single lab\",\n      \"pmids\": [\"36061751\"],\n      \"is_preprint\": false\n    }\n  ],\n  \"current_model\": \"TRIM38 is a RING-domain-containing E3 ubiquitin ligase that acts as a multifunctional negative regulator of innate immune and inflammatory signaling: it promotes K48-linked proteasomal degradation of key signaling adaptors (TRIF, RIG-I, TRAF6, GLUT1, MITA/STING, CCT6A, p53) and K48-linked or lysosome-dependent degradation of TAB2/3, while also catalyzing K63-linked stabilizing ubiquitination (HSPA5, SQSTM1) and competing with TRIM25 for RIG-I binding to limit IFN-I production, collectively restraining TLR3/4-, TNFα/IL-1β-, and RNA/DNA sensor-mediated inflammatory and antiviral signaling.\"\n}\n```","stage2_raw":"```json\n{\n  \"mechanistic_narrative\": \"TRIM38 is a RING-domain E3 ubiquitin ligase that serves as a broad negative regulator of innate immune, inflammatory, and proliferative signaling by targeting multiple pathway adaptors for degradation. It catalyzes K48-linked polyubiquitination and proteasomal degradation of TRIF, RIG-I, TRAF6, MITA/STING, CCT6A, GLUT1, and p53, while independently promoting lysosome-dependent degradation of TAB2/TAB3 through a mechanism that does not require its ligase activity [PMID:24434549, PMID:26392463, PMID:23056470, PMID:38630167, PMID:39033726, PMID:38012139, PMID:40047371, PMID:34906161, PMID:40059473]. TRIM38 also catalyzes K63-linked ubiquitination that stabilizes HSPA5 to promote M2 macrophage polarization and modifies SQSTM1/p62 at K420 to impede autophagic flux [PMID:40300357, PMID:41347593]. Through these activities, TRIM38 restrains TLR3/4-, TNFα/IL-1β-, and cytosolic nucleic acid sensor-mediated signaling, limits NF-κB and MAPK activation in diverse contexts including osteoclastogenesis and cardiac hypertrophy, and restricts Zika virus replication via lysosomal degradation of the NS3 protein [PMID:29753717, PMID:40314083, PMID:40006954].\",\n  \"teleology\": [\n    {\n      \"year\": 2011,\n      \"claim\": \"Establishing that TRIM38 possesses intrinsic E3 ubiquitin ligase activity dependent on its RING domain answered the foundational question of whether this TRIM family member is an active enzyme capable of conjugating both K48- and K63-linked ubiquitin chains.\",\n      \"evidence\": \"In vitro and cellular ubiquitination assays with RING domain mutagenesis\",\n      \"pmids\": [\"21306652\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"No endogenous substrates identified at this stage\", \"Self-ubiquitination function unclear\", \"No in vivo confirmation\"]\n    },\n    {\n      \"year\": 2012,\n      \"claim\": \"Identification of TRIF as a direct K48-linked ubiquitination substrate of TRIM38 established the first mechanistic link between TRIM38 and innate immune signaling, showing it negatively regulates TLR3 signaling by degrading a key adaptor.\",\n      \"evidence\": \"Co-IP, domain mapping (PRYSPRY–TRIF N-terminus), K48 ubiquitination assays, proteasome inhibition in overexpression/knockdown systems\",\n      \"pmids\": [\"23056470\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"Single lab, no in vivo validation at this point\", \"Specific ubiquitination site on TRIF not mapped\"]\n    },\n    {\n      \"year\": 2014,\n      \"claim\": \"Discovery that TRIM38 promotes lysosomal degradation of TAB2/TAB3 independently of its E3 ligase activity revealed a second, non-canonical degradation mechanism by which TRIM38 suppresses TNFα/IL-1β-triggered NF-κB activation.\",\n      \"evidence\": \"Reciprocal Co-IP, KO cells, lysosome inhibitor rescue, NF-κB reporter assays\",\n      \"pmids\": [\"24434549\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Mechanism of lysosome targeting without ubiquitination unresolved\", \"No structural basis for TAB2/3 recognition\"]\n    },\n    {\n      \"year\": 2015,\n      \"claim\": \"In vivo validation using Trim38 knockout mice confirmed TRIM38 as a physiological negative regulator of TLR3/4 signaling (via TRIF K228 ubiquitination) and TNFα/IL-1β signaling (via IFN-induced TAB2 degradation), establishing a type I IFN-driven feedback loop.\",\n      \"evidence\": \"Trim38 KO mice challenged with LPS, poly(I:C), and Salmonella; K48 ubiquitination at K228; IFN priming experiments\",\n      \"pmids\": [\"26392463\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Relative contribution of TRIF vs TAB2 arms in vivo not dissected\", \"Upstream regulation of TRIM38 expression beyond IFN incompletely characterized\"]\n    },\n    {\n      \"year\": 2017,\n      \"claim\": \"Showing that NLRP6 acts as a scaffold to facilitate TRIM38–TAB2/3 interaction in rheumatoid arthritis synoviocytes revealed how TRIM38 activity can be modulated by accessory proteins in disease-specific contexts.\",\n      \"evidence\": \"Co-IP and overexpression in RA fibroblast-like synoviocytes with cytokine readouts\",\n      \"pmids\": [\"28295271\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"Single lab, not replicated in other cell types\", \"Direct vs indirect scaffolding not biochemically resolved\"]\n    },\n    {\n      \"year\": 2018,\n      \"claim\": \"Extension of the TAB2 degradation mechanism to osteoclast biology demonstrated TRIM38 inhibits RANKL-induced osteoclastogenesis and promotes osteoblast differentiation via NF-κB suppression, broadening TRIM38's physiological scope beyond innate immunity.\",\n      \"evidence\": \"Overexpression/knockdown in osteoclast/osteoblast precursors, NF-κB reporters, differentiation markers\",\n      \"pmids\": [\"29753717\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"No in vivo bone phenotype reported\", \"Contribution relative to other TRIM E3s in bone homeostasis unknown\"]\n    },\n    {\n      \"year\": 2021,\n      \"claim\": \"Identification of GLUT1 as a TRIM38 ubiquitination substrate linked TRIM38 to metabolic regulation, showing it suppresses glycolysis and tumor growth in bladder cancer by degrading the glucose transporter.\",\n      \"evidence\": \"TAP/MS substrate discovery, Co-IP, ubiquitination assay, xenograft models\",\n      \"pmids\": [\"34906161\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"Ubiquitin linkage type and site on GLUT1 not specified\", \"Mechanism of TRIM38 downregulation in tumors not defined\"]\n    },\n    {\n      \"year\": 2022,\n      \"claim\": \"Demonstration that TRIM38 degrades TRAF6 to inactivate the TAK1/NF-κB axis in cardiomyocytes, with TAK1 inhibitor rescuing TRIM38-deficiency phenotypes, established TRIM38 as cardioprotective during ischemia-reperfusion injury.\",\n      \"evidence\": \"Adenoviral OE/KD in H9c2 cells under hypoxia/reoxygenation, TAK1 inhibitor epistasis\",\n      \"pmids\": [\"36061751\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"In vitro H/R model only; no in vivo cardiac ischemia model at this stage\", \"Ubiquitin linkage on TRAF6 not confirmed here\"]\n    },\n    {\n      \"year\": 2023,\n      \"claim\": \"Showing TRIM38 K48-ubiquitinates MITA/STING in M2 macrophages to inhibit pyroptosis at the maternal-fetal interface expanded the substrate repertoire to the cGAS-STING pathway and revealed cell-type-specific regulation of TRIM38 activity.\",\n      \"evidence\": \"Co-IP, K48 ubiquitination assays, macrophage polarization, pyroptosis assays\",\n      \"pmids\": [\"38012139\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"Mechanism governing differential TRIM38 activity in M1 vs M2 not elucidated\", \"No in vivo pregnancy model\"]\n    },\n    {\n      \"year\": 2024,\n      \"claim\": \"Discovery that TRIM38 competes with TRIM25 for overlapping RIG-I binding sites, promoting K48 degradation of RIG-I instead of K63 activation, defined a direct antagonistic regulatory circuit controlling IFN-I production via the same sensor.\",\n      \"evidence\": \"Co-IP, domain mapping of RIG-I aa 25–43, K48/K63 ubiquitination assays, IFN-β reporters\",\n      \"pmids\": [\"38630167\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"Competition dynamics not quantified biochemically\", \"In vivo viral challenge with TRIM38 manipulation not performed\"]\n    },\n    {\n      \"year\": 2024,\n      \"claim\": \"Confirmation that TRIM38 K48-ubiquitinates TRAF6 in RANKL-stimulated osteoclasts reinforced TRAF6 as a bona fide TRIM38 substrate and connected TRIM38 to pharmacological modulation of osteoclastogenesis.\",\n      \"evidence\": \"Co-IP, K48 ubiquitination assays, TRIM38 siRNA knockdown, TRAP staining, bone resorption assay\",\n      \"pmids\": [\"39033726\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"No in vivo bone loss model\", \"Precise ubiquitination sites on TRAF6 not mapped\"]\n    },\n    {\n      \"year\": 2025,\n      \"claim\": \"A burst of substrate discoveries (CCT6A, p53, HSPA5, SQSTM1/p62, Zika NS3, TRAF6 crotonylation-enhanced degradation) and in vivo cardiac hypertrophy phenotyping dramatically expanded TRIM38's known target repertoire and functional contexts, including autophagy regulation, cancer suppression, antiviral defense, and cardiac remodeling.\",\n      \"evidence\": \"Site-specific mutagenesis (CCT6A K127/K138, SQSTM1 K420, TRIM38 K142), Trim38 KO mouse TAC model with TAK1 epistasis, TRIM38 KO cells for ZIKV, crotonylation proteomics, autophagy flux assays, in vivo tumor models\",\n      \"pmids\": [\"40047371\", \"40059473\", \"40300357\", \"41347593\", \"40006954\", \"40332097\", \"40314083\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"Most findings from single labs awaiting independent replication\", \"Structural basis for TRIM38 substrate selectivity across diverse targets unknown\", \"Relative physiological importance of K63 stabilizing vs K48 degradative activities not determined\"]\n    },\n    {\n      \"year\": null,\n      \"claim\": \"How TRIM38 achieves substrate selectivity across its remarkably diverse target repertoire, and how its ligase-dependent (K48/K63 ubiquitination) and ligase-independent (lysosomal targeting) activities are differentially engaged in specific cellular contexts, remain open mechanistic questions.\",\n      \"evidence\": \"\",\n      \"pmids\": [],\n      \"confidence\": \"High\",\n      \"gaps\": [\"No structural model of TRIM38–substrate complexes\", \"Post-translational regulation of TRIM38 (beyond IFN induction and crotonylation) incompletely mapped\", \"Comprehensive in vivo phenotyping across immune, metabolic, and developmental contexts lacking\"]\n    }\n  ],\n  \"mechanism_profile\": {\n    \"molecular_activity\": [\n      {\"term_id\": \"GO:0140096\", \"supporting_discovery_ids\": [1, 2, 3, 4, 7, 8, 9, 10, 12, 14, 15, 16]},\n      {\"term_id\": \"GO:0016874\", \"supporting_discovery_ids\": [1, 2, 3, 4, 7, 8, 9, 10, 14, 15, 16]}\n    ],\n    \"localization\": [\n      {\"term_id\": \"GO:0005829\", \"supporting_discovery_ids\": [0, 2]}\n    ],\n    \"pathway\": [\n      {\"term_id\": \"R-HSA-168256\", \"supporting_discovery_ids\": [0, 1, 2, 4, 6, 8, 11, 15]},\n      {\"term_id\": \"R-HSA-162582\", \"supporting_discovery_ids\": [0, 1, 5, 13, 16, 17]},\n      {\"term_id\": \"R-HSA-392499\", \"supporting_discovery_ids\": [1, 2, 3, 7, 9, 12, 14, 15, 16]},\n      {\"term_id\": \"R-HSA-9612973\", \"supporting_discovery_ids\": [14]},\n      {\"term_id\": \"R-HSA-5357801\", \"supporting_discovery_ids\": [8]}\n    ],\n    \"complexes\": [],\n    \"partners\": [\n      \"TAB2\",\n      \"TAB3\",\n      \"TRIF\",\n      \"TRAF6\",\n      \"RIG-I\",\n      \"MITA\",\n      \"CCT6A\",\n      \"SQSTM1\"\n    ],\n    \"other_free_text\": []\n  }\n}\n```"}